A Prospective Study of Leukocyte Telomere Length and Risk of Renal Cell Carcinoma

Hofmann, Jonathan N.; Lan, Qing; Cawthon, Richard M.; Hosgood, Dean; Shuch, Brian; Moore, Lee E.; Rothman, Nathaniel; Chow, Wong‐Ho; Purdue, Mark P.

doi:10.1158/1055-9965.epi-13-0142

Cited by 15 publications

(17 citation statements)

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“…Results of studies of leukocyte telomere length and risk of renal cell carcinoma (RCC) have been inconsistent. Two small hospital-based case-control studies reported inverse associations between telomere length and risk of RCC [10,11], whereas no significant evidence of an association was observed in a larger population-based case-control study [12] and two cohort-based investigations using prediagnostic samples [13,14]. In contrast, longer leukocyte telomere length has been associated with reduced RCC survival [15].…”

Section: Introductionmentioning

confidence: 99%

“…Leukocyte telomere length measurements in case-control studies, using postdiagnosis blood samples, may have been influenced by effects of the disease. All studies measured telomere length from a single time point, which may not adequately reflect telomere length status in the etiologically relevant time window, and were susceptible to confounding from RCC risk factors that may be associated with telomere length such as smoking [13,18] and obesity [19]. Furthermore, qPCR-based measurements of telomere length are sensitive to preanalytic factors such as DNA source material and extraction method [12,20,21].…”

Section: Introductionmentioning

confidence: 99%

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Genetic Variants Related to Longer Telomere Length are Associated with Increased Risk of Renal Cell Carcinoma

et al. 2017

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Background Relative telomere length in peripheral blood leukocytes has been evaluated as a potential biomarker for renal cell carcinoma (RCC) risk in several studies, with conflicting findings. Objective We performed an analysis of genetic variants associated with leukocyte telomere length to assess the relationship between telomere length and RCC risk using Mendelian randomization, an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations. Design, setting, and participants Genotypes from nine telomere length-associated variants for 10 784 cases and 20 406 cancer-free controls from six genome-wide association studies (GWAS) of RCC were aggregated into a weighted genetic risk score (GRS) predictive of leukocyte telomere length. Outcome measurements and statistical analysis Odds ratios (ORs) relating the GRS and RCC risk were computed in individual GWAS datasets and combined by meta-analysis. Results and limitations Longer genetically inferred telomere length was associated with an increased risk of RCC (OR = 2.07 per predicted kilobase increase, 95% confidence interval [CI]: = 1.70–2.53, p < 0.0001). As a sensitivity analysis, we excluded two telomere length variants in linkage disequilibrium (R2 > 0.5) with GWAS-identified RCC risk variants (rs10936599 and rs9420907) from the telomere length GRS; despite this exclusion, a statistically significant association between the GRS and RCC risk persisted (OR = 1.73, 95% CI = 1.36–2.21, p < 0.0001). Exploratory analyses for individual histologic subtypes suggested comparable associations with the telomere length GRS for clear cell (N = 5573, OR = 1.93, 95% CI = 1.50–2.49, p < 0.0001), papillary (N = 573, OR = 1.96, 95% CI = 1.01–3.81, p = 0.046), and chromophobe RCC (N = 203, OR = 2.37, 95% CI = 0.78–7.17, p = 0.13). Conclusions Our investigation adds to the growing body of evidence indicating some aspect of longer telomere length is important for RCC risk. Patient summary Telomeres are segments of DNA at chromosome ends that maintain chromosomal stability. Our study investigated the relationship between genetic variants associated with telomere length and renal cell carcinoma risk. We found evidence suggesting individuals with inherited predisposition to longer telomere length are at increased risk of developing renal cell carcinoma.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Genetic Variants Related to Longer Telomere Length are Associated with Increased Risk of Renal Cell Carcinoma

et al. 2017

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“…Telomere shortening has been proved to be a risk factor in many sporadic and hereditary cancers, including Lynch syndrome, hereditary prostate cancer, familial, and sporadic ovarian cancer. As to RCC, two hospital‐based case–control studies demonstrated that short leukocyte telomere length was associated with increased sporadic RCC risk, while a large population‐based study drew different conclusions . Svenson et al.…”

Section: Discussionmentioning

confidence: 99%

“…Critically short telomeres lead to genetic instability and increase risks of age‐related disease including cancers . Peripheral blood leukocyte telomere length has been reported to be a potential biomarker of tumor risk for various types of familiar and sporadic tumors, including hereditary non‐polyposis colorectal cancer(Lynch syndrome), hereditary prostate cancer, familial and sporadic ovarian cancer, renal cell carcinoma and pancreatic cancer . VHL disease seems similar to some hereditary disease such as Lynch syndrome, and shorter telomere length contributes to the earlier onset age in the next generations than their parental generations within VHL families.…”

Section: Introductionmentioning

confidence: 99%

Shorter telomere length increases age‐related tumor risks in von Hippel‐Lindau disease patients

et al. 2017

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Von Hippel‐Lindau (VHL) disease is a rare autosomal dominant cancer syndrome caused by alterations of VHL gene. Patients are predisposed to develop pheochromocytomas and solid or cystic tumors of the central nervous system, kidney, pancreas, and retina. Remarkable phenotypic heterogeneity exits in organ involvement and tumor onset age between and within VHL families. However, no reliable markers have been found to predict the age‐related tumor risks in VHL patients. A large Chinese cohort composed of 300 VHL patients and 92 healthy family controls was enrolled in our study. Blood relative telomere length was measured in 184 patients and all the controls available for genomic DNA samples. Age‐related risks for the five major VHL‐associated tumors were evaluated using Kaplan–Meier plots and Cox regression analysis. Differences in clinical phenotype were observed between Chinese cohort and the United Kingdom cohort. VHL patients showed significantly shorter telomere length than healthy family controls(P = 0.0183), and a positive correlation was found between telomere length and onset age of the five major tumors, respectively. Moreover, patients in the shorter telomere group (age‐adjusted telomere length ≤ 0.44) suffered higher age‐related risks for VHL‐associated central nervous system hemangioblastomas (HR: 1.879, P = 0.004), renal cell carcinoma (HR: 2.126, P = 0.002) and pancreatic cyst and neuroendocrine tumors (HR: 2.093, P = 0.001). These results indicate that blood shorter telomere length is a new biomarker for age‐related tumor risks in VHL patients, which will be crucial to genetic counseling and future research about the role of telomere shortening in the pathogenesis of VHL‐associated tumors.

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“…36 Hoffman et al also conducted two case-control studies, one of them prospective. 63 In both studies, no differences between cases and controls' TL were found, as well as no associations between TL and tumor stage. 63,64 Interestingly, these two studies are the ones which display the biggest sample size of all the case-control studies.…”

Section: Literature Review and Data Collectionmentioning

confidence: 74%

<p>Telomere Length in Renal Cell Carcinoma: The Jekyll and Hyde Biomarker of Ageing of the Kidney</p>

Morais¹,

Dias²,

Teixeira³

et al. 2020

CMAR

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Renal cell carcinoma (RCC) is a heterogeneous group of cancers where the clear cell (ccRCC) is the most common and the most lethal. The absence of accurate diagnostic and follow-up biomarkers along with the time-limited response to therapies may explain the lethality and shows the necessity of new sensitive and specific biomarkers. One of the most studied molecules are the telomeres: specialized ribonucleoprotein structures that keep the structural integrity of the genome. Among other features, telomere length (TL) has been widely studied in several tumor models regarding its biomarker potential, due to the easy detection and quantification. The scope of this review was to analyze all the information about this parameter in RCC. There was some disparity in the results of the studies, since some pointed to an association between short TL and risk or poor outcome of RCC; others between long TL and RCC outcome and some did not find any association. We propose some epidemiological and biological explanations to these differences. The telomeres may play a dual role during RCC carcinogenesis in the early stages, short telomeres may increase RCC risk and in late carcinogenesis, long telomeres seem to be associated with tumor prognosis. However, the controversy of the results along with the lack of specificity are some problems that need to be clarified for the usage of TL as a prognostic biomarker.

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A Prospective Study of Leukocyte Telomere Length and Risk of Renal Cell Carcinoma

Cited by 15 publications

References 8 publications

Genetic Variants Related to Longer Telomere Length are Associated with Increased Risk of Renal Cell Carcinoma

Genetic Variants Related to Longer Telomere Length are Associated with Increased Risk of Renal Cell Carcinoma

Shorter telomere length increases age‐related tumor risks in von Hippel‐Lindau disease patients

<p>Telomere Length in Renal Cell Carcinoma: The Jekyll and Hyde Biomarker of Ageing of the Kidney</p>

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